Quinoline compounds suitable for treating disorders that respond to modulation of the serotonin-5-HT6 receptor

Abstract

The present invention relates to novel quinoline compounds of the formula (I) and to the salts thereof. The compounds possess valuable therapeutic properties and are particularly suitable, for treating diseases that respond to modulation of the serotonin 5-HT 6 receptor. In formula (I) R is a moiety of the formula (R) wherein * indicates the binding site to the quinolinyl radical and wherein A, B, X′, Y, Q, R 1 , R 2 , R 3 , R 4 , R 5 , m, n, p, q, R a , R b , X and Ar are as defined in claim 1 .

We claim: 
     
       1. A method for treating a cognitive dysfunction associated with Alzheimer's disease, a cognitive dysfunction associated with schizophrenia, or obesity, said method comprising administering an effective amount of the compound of formula (I) or a physiologically tolerated acid addition salt or a N-oxide thereof to a subject in need thereof 
       
         
           
           
               
               
           
         
         where in formula (I) 
         R is a radical selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         wherein * indicates the binding site to the quinolinyl radical; 
         R 1  is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -hydroxyalkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 6 -haloalkoxy-C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl, aryl-C 1 -C 4 -alkyl, hetaryl-C 1 -C 4 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -haloalkenyl, formyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl, where the phenyl rings in the last two mentioned moieties are unsubstituted or carry 1, 2 or 3 substituents, selected from halogen, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl; 
         n is 0, 1 or 2; 
         m is 0, 1, 2 or 3; 
         R a , R ib  are independently selected from the group consisting of halogen, CN, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C(O)R aa , C(O)NR cc R bb  and NR cc R bb ;
 wherein R aa  is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy or C 1 -C 4 -haloalkoxy, and 
 R cc , R bb  are independently selected from the group consisting of hydrogen and C 1 -C 4 -alkyl; 
 
         X is S(O) 2 ; which is located in the 3- or 4-position of the quinoline ring; 
         Ar is phenyl, which is unsubstituted or may carry 1, 2, 3 substituents R x , wherein 
         R x  is halogen, CN, NO 2 , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -hydroxyalkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 3 -C 6 -cyclo-alkyl, C 3 -C 6 -halocycloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -hydroxyalkoxy, C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkylthio, C 1 -C 6 -haloalkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -haloalkylsulfinyl, C 1 -C 6 -alkylsulfonyl, C 1 -C 6 -haloalkylsulfonyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, C 1 -C 6 -alkylcarbonylamino, C 1 -C 6 -haloalkyl-carbonylamino, carboxy, NH—C(O)—NR x1 R x2 , NR x1 R x2 , NR x1 R x2 —C 1 -C 6 -alkylene, O—NR x1 R x2 , wherein R x1  and R x2  in the last 4 mentioned radicals are independently of each other hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl or C 1 -C 6 -alkoxy or R x1  and R x2  in the last 4 mentioned radicals together with the nitrogen atom form an N-bound 5-, 6- or 7-membered, saturated heteromonocycle or an N-bound 7-, 8-, 9- or 10-membered, saturated heterobicycle which are unsubstituted or which carry 1, 2, 3 or 4 radicals selected from C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -hydroxyalkyl and C 1 -C 4 -alkoxy and wherein 2 radicals R x , which are bound to adjacent carbon atoms of Ar may form a saturated or unsaturated 5- or 6-membered carbocyclic or heterocyclic ring, which itself may carry a radical R x . 
       
     
     
       2. The method of  claim 1 , wherein R 1  is hydrogen. 
     
     
       3. The method of  claim 1 , wherein X is located in the 3-position of the quinolinyl moiety. 
     
     
       4. The method of  claim 1 , wherein X is located in the 4-position of the quinolinyl moiety. 
     
     
       5. The method of  claim 1 , wherein R x  is selected from the group consisting of halogen, CN, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 3 -C 6 -cycloalkyl and a group NR x1 R x2 . 
     
     
       6. The method of  claim 1 , wherein m is 0. 
     
     
       7. The method of  claim 1 , wherein n is 0. 
     
     
       8. The method of  claim 1 , where the compound of formula (I) is a compound of the formula (Ia.a) 
       
         
           
           
               
               
           
         
         wherein R is a radical R-12 or R-16 
       
       
         
           
           
               
               
           
         
         wherein R 1  is hydrogen and wherein Ar is as defined in  claim 1 . 
       
     
     
       9. The method of  claim 8  where R in formula (Ia.a) is a radical of the formula R-16b, 
       
         
           
           
               
               
           
         
         wherein R 1  is hydrogen. 
       
     
     
       10. The method of  claim 1 , where the compound of formula (I) is a compound of the formula (Ia.a) 
       
         
           
           
               
               
           
         
         wherein m is 0, n is 0 and wherein R is a radical R-16b 
       
       
         
           
           
               
               
           
         
         wherein R 1  is hydrogen or methyl 
         and wherein Ar is selected from the group consisting of phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 3-difluoromethylphenyl, 4-(oxazol-5-yl)phenyl, 3-(oxazol-2-yl)phenyl, 3-(oxazol-4-yl)phenyl and 3-(oxazol-5-yl)phenyl. 
       
     
     
       11. The method of  claim 1 , where the compound of formula (I) or a physiologically tolerated acid addition salt or a N-oxide thereof is administered as a pharmaceutical composition comprising the compound of formula (I) or a physiologically tolerated acid addition salt or a N-oxide thereof together with at least one physiologically acceptable carrier or auxiliary substance. 
     
     
       12. The method of  claim 1 , wherein R x  is selected from the group consisting of halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -hydroxyalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 6 -haloalkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl and a group NR x1 R x2 . 
     
     
       13. The method of  claim 1 , wherein the compound of formula (I), or a physiologically tolerated acid addition salt or a N-oxide thereof, is selected from the group consisting of:
 8-(Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-3-(phenylsulfonyl)quinoline; 
 Benzyl 6-(3-(phenylsulfonyl)quinolin-8-yl)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate; 
 tert-butyl 2-(3-(phenylsulfonyl)quinolin-8-yl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate; 
 3-(Phenylsulfonyl)-8-(1H-pyrrolo[3,4-c]pyridin-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)quinoline; 
 (1R,5S)-tert-butyl 3-(3-(phenylsulfonyl)quinolin-8-yl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate; 
 8-((1S,5S)-3,6-diazabicyclo[3.2.0]heptan-3-yl)-3-(phenylsulfonyl)quinoline; 
 (3aS,6aS)-ethyl 1-(3-(phenylsulfonyl)quinolin-8-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate; 
 tert-butyl 5-(3-(4-fluorophenylsulfonyl)quinolin-8-yl)hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate; 
 tert-butyl 5-(3-(phenylsulfonyl)quinolin-8-yl)octahydro-1,5-naphthyridine-1(2H)-carboxylate; 
 1-(3-(phenylsulfonyl)quinolin-8-yl)decahydro-1,5-naphthyridine; 
 tert-butyl 2-(3-(4-fluorophenylsulfonyl)quinolin-8-yl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate; 
 8-((3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-3-(phenylsulfonyl)quinoline; 
 3-(4-fluorophenylsulfonyl)-8-(1H-pyrrolo[3,4-c]pyridin-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)quinoline; 
 3-(4-fluorophenylsulfonyl)-8-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)quinoline; 
 tert-butyl 5-(3-(3-(trifluoromethoxy)phenylsulfonyl)quinolin-8-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; 
 8-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(3-(trifluoromethoxy)phenylsulfonyl)quinoline; 
 tert-butyl 5-(3-(3-(5-(tert-butoxycarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenylsulfonyl)quinolin-8-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; 
 8-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenylsulfonyl)quinoline; 
 tert-butyl 2-(3-(3-(trifluoromethoxy)phenylsulfonyl)quinolin-8-yl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate; 
 8-(1H-pyrrolo[3,4-c]pyridin-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-3-(3-(trifluoromethoxy)phenylsulfonyl)quinoline; 
 tert-butyl 5-(3-(3-(trifluoromethyl)phenylsulfonyl)quinolin-8-yl)hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate; 
 8-(hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline; 
 (3aR,6aS)-tert-butyl 5-(3-(3-(trifluoromethyl)phenylsulfonyl)quinolin-8-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; 
 8-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline; 
 (3aS,6aS)-ethyl-1-(3-(3-fluorophenylsulfonyl)quinolin-8-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate; 
 3-(3-Fluoro-benzenesulfonyl)-8-(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1-yl-quinoline; 
 (1S,5R)-tert-butyl 3-(3-(3-fluorophenylsulfonyl)quinolin-8-yl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate; 
 8-(1R,5R)-3,6-Diaza-bicyclo[3.2.0]hept-3-yl-3-(3-fluoro-benzenesulfonyl)-quinoline; 
 3-(3-Fluoro-benzenesulfonyl)-8-(hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-quinoline; 
 3-(3-Fluoro-benzenesulfonyl)-8-(3aR,6aS)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl-quinoline; 
 3-(3-fluorophenylsulfonyl)-8-(tetrahydro-1H-pyrrolo[3,4-b]pyridin-6(2H,7H,7aH)-yl)quinoline; 
 8-((1S,5S)-3,6-diazabicyclo[3.2.0]heptan-3-yl)-3-(3-fluorophenylsulfonyl)quinoline; 
 5-(3-(3-fluorophenylsulfonyl)quinolin-8-yl)octahydro-1H-pyrrolo[3,4-c]pyridin-2-ium chloride; 
 8-(5-benzyl-1H-pyrrolo[3,4-c]pyridin-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-3-(3-fluorophenylsulfonyl)quinoline; 
 3-(3-Fluoro-benzenesulfonyl)-8-(octahydro-pyrrolo[3,4-c]pyridin-2-yl)-quinoline; 
 8-((3aS,6aS)-1-benzyl hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-3-(3-fluorophenylsulfonyl)quinoline; 
 3-(3-Fluoro-benzenesulfonyl)-8-((3aR,6aS)-5-methyl-hexahydropyrrolo[3,4-c]pyrrol-2-yl)-quinoline; 
 3-(4-fluorophenylsulfonyl)-8-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)quinoline; 
 3-(4-fluorophenylsulfonyl)-8-(hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)quinoline; 
 8-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(phenylsulfonyl)-quinoline; 
 8-(5-methyl-1H-pyrrolo[3,4-c]pyridin-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-3-(phenylsulfonyl)quinoline; 
 2-(3-(phenylsulfonyl)quinolin-8-yl)dodecahydro-1H-pyrido[4,3-b]indole; 
 8-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(phenylsulfonyl)quinoline; and 
 8-(1H-pyrrolo[3,4-c]pyridin-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-3-(3-(trifluoromethyl)phenylsulfonyl)quinolone.